Long-term outcomes of congenital cytomegalovirus infection in Sweden and the United Kingdom.

BACKGROUND: Congenital cytomegalovirus (CMV) is an important cause of neurological problems, particularly sensorineural hearing loss, but data on long-term sequelae and the impact of nonprimary maternal infection are limited. We report updated findings on childhood outcomes from 2 large prospective studies. METHODS: Pregnant women in Malmö, Sweden, and London, United Kingdom, were included between 1977 and 1986, and newborns were screened for CMV (virus culture of urine or saliva). Cases and matched controls underwent regular, detailed developmental assessments up to at least age 5 years. RESULTS: One hundred seventy-six congenitally infected infants were identified among >50 000 screened (Malmö: 76 [4.6/1000 births]; London: 100 [3.2/1000 births]); 214 controls were selected. Symptoms were recorded in 11% of CMV-infected neonates (19/176) and were mostly mild; only 1 neonate had neurological symptoms. At follow-up, 7% of infants (11/154) were classified as having mild, 5% (7/154) moderate, and 6% (9/154) severe neurological sequelae. Four of 161 controls (2%) had mild impairment. Among children symptomatic at birth, 42% (8/19) had sequelae, versus 14% (19/135) of the asymptomatic infants (P = .006). All moderate/severe outcomes were identified by age 1; mild sequelae were first identified at age 2-5 years in 6 children, and age 6-7 years in 3. Among the 16 children with moderate/severe outcomes, 2 had mothers with confirmed and 7 with presumed nonprimary infection. CONCLUSIONS: Moderate or severe outcomes were reported in 11% of children with congenital CMV identified through population screening, all by 1 year; all impairment detected after this age was mild. Nonprimary infections contributed substantially to the burden of childhood congenital CMV disease.

Tick-borne encephalitis is associated with low levels of interleukin-10 in cerebrospinal fluid.

Tick-borne encephalitis (TBE) is associated with higher morbidity and induces a stronger intrathecal immune activation than most other viral induced meningo-encephalitis. The aim of this study was to investigate cytokine concentrations in cerebrospinal fluid (CSF) and serum in relation to aetiology and clinical course. Cytokines were analysed by Enzyme-linked Immuno Assay (ELISA) from 44 patients with TBE and from 36 patients with aseptic meningo-encephalitis of other aetiology (non-TBE). Significantly increased CSF levels of Interferon-γ (IFN-γ), Interleukin-10 (IL-10), Interleukin-6 (IL-6), Interleukin-1 receptor antagonist (IL-1ra), and soluble CD8 receptor (sCD8) were detected in both cohorts. Tumour necrosis factor-α (TNF-α showed low levels or was not detected in CSF in any group in the acute stage. However, the CSF levels of IL-10 were significantly lower in TBE than in non-TBE cases 0-6 days after onset of encephalitis. The TBE patients with encephalitis had significantly lower IL-10 CSF levels later in the clinical course (day 7-18) than TBE patients with meningeal disease. Increased IFN-γ production, but low IL-10 secretion, may be of pathophysiological significance in TBE.

Serum levels of rubella-specific antibodies in Swedish women following three decades of vaccination programmes.

In Sweden, more than 30 years after the introduction of vaccination for 12-year-old girls and post-partum mothers against rubella and 22 years after the introduction of routine MMR vaccination for all children at the ages of 18 months and 12 years, we have evaluated the rubella IgG activity in antenatal sera. 95.8% (39,890/41,637) of all women had anti-rubella IgG levels >or=10IU/mL. Levels <10IU/mL were more frequent in certain subcohorts: 8.2% (153/1870) of the Swedish women born after the introduction of the programme of childhood vaccination, 7.7% (616/8025) of women born outside the Nordic countries and 10.2% (118/1155) of recent immigrants and refugees to Sweden. In order to attain the goal of protecting the unborn, we propose alternative strategies to be evaluated: routine screening for rubella immunity prior to the first pregnancy, offering individuals with uncertain immunity a booster dose, and/or routine administration of an additional dose of MMR vaccine to all young adults before they leave the educational system.

Prognostic value of intrathecal antibody production and DNA viral load in cerebrospinal fluid of patients with herpes simplex encephalitis.

Herpes simplex encephalitis is a devastating disease. In the early 1980s our group conducted a nationwide clinical trial of acyclovir versus vidarabine in patients with herpes simplex encephalitis in whom intrathecal herpes simplex virus (HSV) antibodies were assayed. The purpose of this study was to investigate if antibody levels and viral load correlate with outcome in herpes simplex encephalitis. We have analysed the prognostic value of HSV antibody levels in serum and cerebrospinal fluid (CSF) at the start of antiviral treatment in the 53 included patients. Frozen samples from a subset of patients were analysed with quantitative polymerase chain reaction (PCR) to assess the prognostic value of the viral load in CSF. IgG-levels in CSF at presentation were significantly higher in vidarabine-treated patients with a favourable outcome than in those treated with vidarabine but with an unfavourable outcome. The intrathecal viral load at presentation showed no correlation with outcome. However, the duration of positive HSV-PCR in CSF was longer in vidarabine-treated than in acyclovir-treated patients. These findings indicate that the B-cell response is important in the pathogenetic process of herpes simplex encephalitis. However, neither antibody levels nor viral load at presentation are useful as prognostic markers for the individual patient in this study.

Neuropsychologic outcomes in children with neonatal herpes encephalitis.

Neonatal herpes simplex virus infection with involvement of the central nervous system is a serious disease with high morbidity, even with acyclovir therapy. The disability includes cerebral palsy and different aspects of cognitive dysfunction which are of utmost importance for the child's future habilitation. We conducted a descriptive cohort study to define neuropsychologic outcomes and determine the relationship between neonatal neuroimaging and neuropsychologic outcomes. Among 267,690 children born in the Stockholm area over 12 years (1989-2000), 14 were diagnosed with neonatal herpes including central nervous system involvement. Nine children were neuropsychologically evaluated. Neonatal herpes virus infection had an even greater impact on cognitive function, speech ability, and attention deficit than anticipated. Relapse leading to deterioration was demonstrated in one child. Social skills were influenced to a lesser degree. Neurodevelopmental outcomes of the children were not well-correlated with extent of cerebral damage as visualized by computed tomography at 7-28 days after onset of signs. Neuropsychologic assessment is essential in the habilitation of the child, and a prerequisite for the evaluation of new treatments and for the assessment of deterioration of cerebral function related to relapses.

Effect of maternal herpes simplex virus (HSV) serostatus and HSV type on risk of neonatal herpes.

BACKGROUND: Neonatal herpes simplex virus (HSV) is a rare but devastating disease. We have conducted pooled analyses of data from 3 cohorts to evaluate the effects of maternal HSV serostatus and HSV type on risk of neonatal HSV acquisition and severity. METHODS: Data from cohorts in Seattle, WA, and Stanford, CA, USA, and Stockholm, Sweden were pooled using Mantel-Haenszel methods. RESULTS: Seventy-eight infants with documented neonatal HSV and known maternal HSV serostatus were included. The risk of neonatal HSV-2 infection was similar in infants born to HSV seronegative women compared with HSV-1 seropositive women (pooled OR: 1.6; 95% CI: 0.6-4.0). The odds of neonatal HSV infection was increased in the presence of exposure to maternal HSV-1 versus HSV-2 (adjusted pooled OR: 19.2; 95% CI: 5.8-63.6). An elevated odds of disseminated HSV in infants born to women with newly acquired genital herpes was observed in Stockholm (OR=13.5; 95% CI: 1.4-630), but not in Seattle or Stanford. CONCLUSION: Our results suggest that maternal HSV-1 antibody offers little, if any, protection against neonatal HSV-2 infection. During reactivation, HSV-1 appears more readily transmissible to the neonate than HSV-2, a concerning finding given the rising frequency of genital HSV-1 infection.

Study of the serological response after vaccination against tick-borne encephalitis in Sweden.

The antibody response to vaccination against tick-borne encephalitis (TBE) with FSME-Immun Inject (Immuno AG/Baxter) was studied in 535 persons, mainly adults, attending a vaccination centre in Stockholm, Sweden. Emphasis was laid on long-term follow-up. Antibody activity was measured by three different serological test systems: a commercial ELISA kit, a hemagglutination inhibition (HI) test and a neutralization test (RFFIT). The neutralization test proved to be the most sensitive assay for the detection of the vaccine response, which was demonstrable in the majority of vaccinees (>90% after three and >98% after four and five vaccinations, respectively). ELISA and HI were less sensitive for antibody measurement during primary immunization. Neutralizing antibody activity persisted prior to the third dose in 77% of the vaccinees and prior to the fourth to sixth doses in 89-95% of the vaccinees. ELISA activity, but no neutralizing activity, was found in some individuals. Based on our data and previous experience of vaccine failures after two doses, a more condensed three-dose vaccination schedule may be advantageous and ought to be tested. The persistence of neutralizing antibodies justifies further studies of the antibody responses after the fourth dose for periods beyond the recommended 3-year booster intervals.

Characterisation of human tick-borne encephalitis virus from Sweden.

Viruses of the tick-borne encephalitis (TBE) antigenic complex, within the family Flaviviridae, cause a variety of diseases including uncomplicated febrile illness, meningo-encephalitis and haemorrhagic fever. Different wildlife species act as reservoir hosts with ixodid tick species as vectors. TBE virus (TBEV) causes 40-130 cases confirmed serologically in Sweden each year. Characteristics of TBEV strains circulating in Sweden have not been investigated previously and no viral sequence data has been reported. In the present study, virus strains were isolated from serum of patients with clinical symptoms consistent with acute TBEV infection. Serologic characterisation, using a panel of E-specific monoclonal antibodies and cross-neutralisation tests, indicated that the Swedish strains of TBEV, isolated 1958-1994, all belonged to the Western TBEV subtype, which includes the Austrian vaccine strain Neudoerfl. Genetic analysis of a partial E-sequence confirmed this close relationship: all Swedish TBEV strains belonged to the European lineage of the Western TBEV subtype, which includes the previously characterised strains Neudoerfl, Hypr, and Kumlinge. Further, three Swedish strains showed partial E-sequences identical to that of the Finnish Kumlinge strain, ten Swedish strains formed a well-supported separate cluster, whereas four others did not show any real clustering. No apparent correlation was observed in comparison of clinical parameters with genetic data or geographic origin of the strains.

Evaluation of an Internet-based database on infectious disorders during pregnancy: INFPREG.

OBJECTIVE: To evaluate the use of an Internet-based information system on infectious disorders (INFPREG) in antenatal care in Sweden. METHODS: A postal questionnaire was sent to all antenatal clinics in Sweden in 2000 (n = 515) and 2002 (n = 503). The questionnaire consisted of sections covering use of computers, availability of Internet connections and the use of INFPREG in patient care. RESULTS: We received 404 completed questionnaires in 2000 and 501 in 2002. In 2000, 81% of the midwives had access to computers at their antenatal clinics, and this number had increased to 93% in 2002. Sixty-eight percent and 88% in 2000 and 2002, respectively, had computers with an Internet connection. Of the responding midwives, 74% in 2000 and 84% in 2002 had received information concerning INFPREG. In 2000, 29% of the midwives had visited INFPREG and this figure had increased to 58% in 2002. Of the midwives that had used INFPREG, 67% in 2000 and 81% in 2002 reported that the information obtained from the site was implemented in the patient care. Of the responders, 45% in 2000 and 43% in 2002 claimed that they needed more information on how to use INFPREG. CONCLUSIONS: A majority of midwives at antenatal clinics in Sweden have access to the Internet and are confident in using an Internet-based knowledge center on infectious disorders in pregnancy. The present study indicates a rapid acceptance among health care providers in antenatal care in Sweden of this new method for dissemination of information and guidelines. However, many midwives still want more information and knowledge on how to use an Internet-based information system.

Detection of herpes simplex virus DNA in dried blood spots making a retrospective diagnosis possible.

BACKGROUND: Herpes simplex virus (HSV) infections in neonates are associated with life-threatening disease. Early diagnosis and treatment with antiviral therapy has decreased the morbidity, mortality and long-term sequelae in surviving children. The aim of the study was to investigate if herpes simplex virus DNA detection in dried blood spots on filter papers (Guthrie cards) sampled for screening of metabolic diseases may contribute to early diagnosis of neonatal HSV infection and enable pre-emptive therapy. METHODS: For detection of HSV-1 and -2 DNA, two different DNA extraction methods were evaluated. A minimal essential medium (MEM) extraction method was found superior and was used in combination with detection of HSV-1 and -2 DNA by PCR in dried blood spots from children with verified neonatal HSV infection. Cards from 28 children were included. The onset of illness varied from day 0 to 42 days and was the result of different types of maternal infection (27 cases) and an external source (one case). RESULTS: HSV DNA was detected in seven of the 28 Guthrie cards, two were HSV-1 and five were HSV-2 DNA positive. Positive dried blood spot cards were sampled within the interval 5 days before, to 6 days after onset of neonatal herpes. In cases of late onset CNS disease, viremia, was not demonstrable at the age of 3-5 days, the time period when the blood spot cards are normally sampled. CONCLUSION: Viremia, the prerequisite for demonstrating HSV DNA in dried blood spot cards preceded the onset of illness by up to 5 days and lasted at least up to 6 days thereafter. Analysis of HSV DNA in dried blood spot cards may be of value in the diagnostic arsenal for early onset of neonatal herpes and also have a role in the follow up of a child exposed at delivery. As the majority of the later onset neonatal herpes encephalitis cases are missed, a large-scale neonatal screening does not seem appropriate.

Neurologic morbidity after herpes simplex virus type 2 meningitis: a retrospective study of 40 patients.

In order to study the long-term course after herpes simplex virus type 2 (HSV-2) meningitis and/or myeloradiculitis the records of 40 consecutive patients were studied. During the year following the acute phase, verified or suspected neurologic recurrences were noted in nearly half of the patients: 1 or more episodes of recurring meningitis were noted in 8 patients; new episodes of myelitis or radiculitis in 3; distinct attacks of headache in 4; and diffuse neurologic complaints impairing daily life in 3. Recurring mucocutaneous symptoms were observed in 16 patients. Eleven patients experienced concurrent or separate episodes of recurring mucocutaneous and neurologic symptoms, 7 had neurologic recurrences only and 5 had only mucocutaneous recurrences. As considerable morbidity may result, patients with HSV-2 meningitis and/or myeloradiculitis should be identified by means of thorough history-taking, careful examination and a specific viral diagnosis in order to enable adequate advice and counseling to be provided and to aid decision-making regarding antiviral therapy.